1. Field of Invention
This invention relates to a method for treating or preventing neuro-degenerative disorders and neuro-developmental disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and the adverse neurologic complications of Down syndrome, as well as neuron death resulting from injury such as stroke, cerebral ischemia, or chemical and/or physical trauma to the central or peripheral nervous system. This invention further relates to the method of increasing the amount of the full-length TrkB isoform polypeptide in neurons to treat or prevent neuro-degenerative disorders and adverse neurologic complications of Down syndrome. This invention also relates to the method of decreasing the amount of the truncated TrkB isoform polypeptide in neurons to treat or prevent neuro-degenerative disorders, as well as the adverse neurologic complications of Down syndrome.
2. Description of the Related Art
Neurotrophins comprise a class of polypeptide neuron survival factors that not only support the survival of post-mitotic neurons (Lewin and Barde, Physiology of the neurotrophins; Ann. Rev. Neurosci. 19:289–317 (1996)), but also regulate other neuronal functions, including, among others, axon growth and synaptic plasticity (Black I B, Trophic regulation of synaptic plasticity; J. Neurobiol. 41:108–118 (1999); Lentz; et al., Neurotrophins support the development of diverse sensory axon morphologies; J. Neurosci. 19:1038–1048 (1999); Lu and Chow, Neurotrophins and hippocampal synaptic transmission and plasticity; J. Neurosci. Res. 58:76–87 (1999); McAllister et al., Neurotrophins and synaptic plasticity, Ann. Rev. Neurosci. 22:295–318 (1999); Schinder and Poo, The neurotrophin hypothesis for synaptic plasticity, Trends Neurosci. 23:639–645 (2000); Thoenen, Neurotrophins and activity-dependent plasticity, Prog. Brain Res. 128:183–191 (2000)). The class of neurotrophins includes, but is not limited to, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). Neurotrophins bind to receptors and activate tyrosine receptor kinases (trks) (Barbacid, The Trk family of neurotrophin receptors, J. Neurobiol. 25:1386–1403 (1994); Bothwell, Functional interactions of neurotrophins and neurotrophin receptors, Ann. Rev. Neurosci. 18:223–253 (1995)). NGF primarily acts via TrkA; BDNF and NT-4/5 primarily via TrkB; and NT-3 primarily via TrkC. However the specificity of these interactions are not absolute. Binding of neurotrophins to trk dimers initiates trans auto-phosphorylation of specific tyrosine residues on the intracellular domain of the receptor (Segal and Greenberg, Intracellular signaling pathways activated by neurotrophic factors, Ann. Rev. Neurosci. 19:463–489 (1996); Kaplan and Miller, Neurotrophin signal transduction in the nervous system, Curr. Opinion Neurobiol. 10:381–391 (2000)). These phospho-tyrosine residues serve as docking sites for elements of intracellular signaling cascades that lead to the suppression of neuron death and other effects of the neurotrophins. TrkB and TrkC are also present as truncated forms which lack the intracellular kinase domain and are, therefore, incapable of normal phosphorylation (Klein et al., The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain, Cell 61:647–656 (1990); Middlemas et al., trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors, Mol. Cell Biol. 11:143–153 (1991); Tsoulfas et al., The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells, Neuron 10:975–990 (1993)). The full-length and truncated trk isoforms are generated by alternative splicing of the primary trk RNA. While there is some evidence that activation of truncated trk receptors can elicit cellular responses independently of normal tyrosine phosphorylation (Baxter et al., Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2, J. Neurosci. 17:2683–2690 (1997); Hapner et al., Neural differentiation promoted by truncated trkC receptors in collaboration with p75(NTR), Dev. Biol. 201:90–100 (1998); Haapasoalo et al., Expression of the naturally occurring truncated trkB neurotrophin receptor induces outgrowth of filopodia and processes in neuroblastoma cells, Oncogene 18:1285–1296 (1999)), truncated trk receptors are generally thought to inhibit trk-mediated neurotrophin signaling by interacting with full-length receptors to form inactive heterodimers (Eide et al., Neurotrophins and their receptors-current concepts and implications for neurological disease, Exp. Neurol. 121:200–214 (1996)). The expression of truncated trk receptors is developmentally regulated (Fryer et al., Developmental and mature expression of full-length and truncated trkB receptors in the rat forebrain, J. Comp. Neurol. 374:21–40 (1996)) and may represent a normal mechanism for modulating the cellular response to specific neurotrophins (Ninkina et al., Expression and function of TrkB variants in developing sensory neurons, EMBO J. 15:6385–6393 (1996)).
The trisomy 16 (Ts16) mouse has a triplication of chromosome 16 (Coyle et al., Down syndrome, Alzheimer's disease and the trisomy 16 mouse, Trends Neurosci. 11:390–394 (1988)). A cassette of approximately 185 genes on human chromosome 21 is located on mouse chromosome 16 (Hattori et al., The chromosome 21 mapping and sequencing consortium (2000) The DNA sequence of human chromosome 21, Nature 405:311–319 (2000)). As such Ts16 mice share a common genetic defect with the human disorder, Down syndrome (trisomy 21; DS) even though some mouse chromosome 16 genes that are not on human chromosome 21 are overexpressed in Ts16 mice. DS is characterized by mental retardation and, in patients over 40 years of age, Alzheimer's disease (AD) (Mann et al., Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes, Neuropathol. Appl. Neurobiol. 10:185–207 (1984)). Neurons from embryonic Ts16 mice undergo accelerated death by apoptosis (Bambrick et al., Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse, Proc. Natl. Acad. Sci. USA 92:9692–9696 (1995); Stabel-Burow et al., Glutathione levels and nerve cell loss in hippocampal cultures from trisomy 16 mouse—a model of Down syndrome, Brain Res. 765:313–318 (1997); Hallam and Maroun, Anti-gamma interferon can prevent the premature death of trisomy 16 mouse cortical neurons in culture, Neurosci. Lett. 252:17–20 (1998); Bambrick and Krueger, Neuronal apoptosis in mouse trisomy 16: mediation by caspases, J. Neurochem. 72:1769–1772 (1999)), as do cultured cortical neurons from DS fetuses (Busciglio and Yankner, Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro, Nature 378:776–779 (1995)). CNS neurons produce BDNF in response to excitatory stimuli. This endogenously produced BDNF mediates activity-dependent neuron survival (Ghosh et al., Requirement for BDNF in activity-dependent survival of cortical neurons, Science 263:1618–1623 (1994)) However, Ts16 hippocampal neurons do not exhibit activity-dependent survival (Bambrick et al., Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse, Proc. Natl. Acad. Sci. USA 92:9692–9696 (1995)). It is possible that the accelerated death of Ts16 neurons results from failure of BDNF signaling.
This invention demonstrates that Ts16 neurons fail to respond to BDNF. This failure accounts for their accelerated death and results from altered expression of a trkB isoform.